The National Institutes of Health has awarded Wayne State University School of Medicine faculty member Zhibing Zhang, MD, Ph.D., a new grant of $2,401,671 over five years to study defects in small organelles called eyelashes which can lead to infertility and other disorders.
Dr. Zhang, associate professor of physiology and obstetrics and gynecology, is the principal investigator of “Intraflagellar transport (IFT) and sperm formation,” funded by the National Institute of Child Health and Human Development Eunice Kennedy Shriver.
“Nearly one in seven couples are infertile, and up to half of these cases are caused by male factor infertility. Genetic factors contribute significantly to male infertility,” Dr. Zhang said. “However, most of these genetic factors are unclear. Mutations in the IFT genes have been reported in infertile patients. Our studies will reveal new genetic factors for male infertility. On the other hand, the results of this research will also identify new targets for the development of male contraceptives.
His co-investigators on the project are Professor of Pharmaceutical Sciences Paul Stemmer, Ph.D., at the Proteomics Core Laboratory, and Associate Professor of Physics Christopher Kelly, Ph.D.
Cilia are small organelles that protrude from the cell surface. They play an indispensable role in the development and functioning of organs. Defects in cilia or cilia-related proteins cause various human pathologies, including male and female infertility, polycystic kidneys, hydrocephalus, vision, hearing loss and more, Dr. Zhang said.
Cilia are formed by an evolutionarily conserved mechanism, intraflagellar transport or IFT. Through IFT, proteins and other components are transported to assemble functional cilia.
Twenty-two basic components of IFT have been identified to date.
“The role of IFT in somatic tissues has been widely studied. However, little is known about its function in reproduction, especially in the formation of sperm flagella, because inactivation of these IFT genes results in the embryonic lethality,” Dr. Zhang said. “Our lab is the first in the world to use the cell/tissue-specific knockout strategy to study the role of IFT in mammalian reproduction, and we have found that all the IFT genes studied so far are essential for male fertility and sperm formation.”
Normal sperm motility is necessary for sperm to fertilize eggs and is largely dependent on the normal development of the sperm flagellum. However, the mechanisms that lead to proper protein targeting and assembly in the sperm flagellum are not fully understood.
Sperm flagella are specialized motile cilia. Compared to cilia in somatic cells, sperm flagella have accessory structures including fibrous sheath, mitochondrial sheath and outer dense fibers, accessory structures necessary for sperm motility.
“We found that IFT25, a component of IFT, is very important for the formation of the accessory structure of sperm. This IFT is not required for the formation of cilia in somatic cells/tissues. We have concluded that IFT25 plays a unique role in normal sperm formation/function by assembling sperm accessory structures. Thus, this project aims to investigate the mechanism by which IFT25 regulates sperm formation and function.” -he declares.
The new project is linked to an older project, in which the lab studied a protein complex found in a unique structure in male germ cells called the cuff. The structure is transient during the development of male germ cells. The structure is enriched in microtubules and F-actins and is thought to provide transport of cargo proteins to the basal bodies for sperm formation via the process called intra-cuff transport.
“The basal body is the starting point for IFT and provides the template for cilia formation,” Dr. Zhang said. “Thus, IFT is the extension of IMT, and the two transport systems are functionally connected.”
The award number for this grant from the National Institutes of Health is R01HD105944.